Antibacterial activity of bacteriophage-encoded endolysins against planktonic and biofilm cells of pathogenic Escherichia coli.

This study was designed to assess the possibility of using bacteriophage-encoded endolysins for controlling planktonic and biofilm cells. The endolysins, LysEP114 and LysEP135, were obtained from plasmid vectors containing the endolysin genes derived from Escherichia coli phages. The high identity (>96%) was observed between LysEP114 and LysEP135. LysEP114 and LysEP135 were characterized by pH, thermal, and lactic acid stability, lytic spectrum, antibacterial activity, and biofilm eradication. The molecular masses of LysEP114 and LysEP135 were 18.2 kDa, identified as muramidases. LysEP114 and LysEP135 showed high lytic activity against the outer membrane-permeabilized E. coli KCCM 40405 at below 37°C, between pH 5 to 11, and below 70 mM of lactic acid. LysEP114 and LysEP135 showed the broad rang of lytic activity against E. coli KACC 10115, S. Typhimurium KCCM 40253, S. Typhimurium CCARM 8009, tetracycline-resistant S. Typhimurium, polymyxin B-resistant S. Typhimurium, chloramphenicol-resistant S. Typhimurium, K. pneumoniae ATCC 23357, K. pneumoniae CCARM 10237, and Shigella boydii KACC 10792. LysEP114 and LysEP135 effectively reduced the numbers of planktonic E. coli KCCM by 1.7 and 2.1 log, respectively, when treated with 50 mM lactic acid. The numbers of biofilm cells were reduced from 7.3 to 4.1 log CFU/ml and 2.2 log CFU/ml, respectively, when treated with LysEP114- and LysEP135 in the presence of 50 mM lactic acid. The results suggest that the endolysins in combination with lactic acid could be potential alternative therapeutic agents for controlling planktonic and biofilm cells.

Androgen-responsive FOXP4 is a target for endometrial carcinoma.

Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.

Protocol for the Adolescent Menstrual Experiences and Health Cohort (AMEHC) Study in Khulna, Bangladesh: A Prospective cohort to quantify the influence of menstrual health on adolescent girls' health and education outcomes.

BACKGROUND: Menstrual health is essential for gender equity and the well-being of women and girls. Qualitative research has described the burden of poor menstrual health on health and education; however, these impacts have not been quantified, curtailing investment. The Adolescent Menstrual Experiences and Health Cohort (AMEHC) Study aims to describe menstrual health and its trajectories across adolescence, and quantify the relationships between menstrual health and girls' health and education in Khulna, Bangladesh. METHODS AND ANALYSIS: AMEHC is a prospective longitudinal cohort of 2016 adolescent girls recruited at the commencement of class 6 (secondary school, mean age=12) across 101 schools selected through a proportional random sampling approach. Each year, the cohort will be asked to complete a survey capturing (1) girls' menstrual health and experiences, (2) support for menstrual health, and (3) health and education outcomes. Survey questions were refined through qualitative research, cognitive interviews and pilot survey in the year preceding the cohort. Girls' guardians will be surveyed at baseline and wave 2 to capture their perspectives and household demographics. Annual assessments will capture schools' water, sanitation and hygiene, and support for menstruation and collect data on participants' education, including school attendance and performance (in maths, literacy). Cohort enrolment and baseline survey commenced in February 2023. Follow-up waves are scheduled for 2024, 2025 and 2026, with plans for extension. A nested subcohort will follow 406 post-menarche girls at 2-month intervals throughout 2023 (May, August, October) to describe changes across menstrual periods. This protocol outlines a priori hypotheses regarding the impacts of menstrual health to be tested through the cohort. ETHICS AND DISSEMINATION: AMEHC has ethical approval from the Alfred Hospital Ethics Committee (369/22) and BRAC James P Grant School of Public Health Institutional Review Board (IRB-06 July 22-024). Study materials and outputs will be available open access through peer-reviewed publication and study web pages.

Impact of extreme weather events on mental health in South and Southeast Asia: A two decades of systematic review of observational studies.

Extreme weather events in South and Southeast Asia exert profound psychosocial impacts, amplifying the prevalence of mental illness. Despite their substantial consequences, there is a dearth of research and representation in the current literature. We conducted a systematic review of observational studies published between January 1, 2000, and January 20, 2024, to examine the impact of extreme weather events on the mental health of the South and Southeast Asian population. Quality assessment of the included studies was conducted using the Newcastle-Ottawa Scale (NOS) quality appraisal checklist. The search retrieved 70 studies that met the inclusion criteria and were included in our review. Most were from India (n = 22), and most used a cross-sectional study design (n = 55). Poor mental health outcomes were associated with six types of extreme weather events: floods, storm surges, typhoons, cyclones, extreme heat, and riverbank erosion. Most studies (n = 41) reported short-term outcome measurements. Findings included outcomes with predictable symptomatology, including post-traumatic stress disorder, depression, anxiety, general psychological distress, emotional distress and suicide. Limited studies on long-term effects showed higher mental disorders after floods and typhoons, while cyclone-exposed individuals had more short-term distress. Notably, the review identified over 50 risk factors influencing mental health outcomes, categorized into six classes: demographic, economic, health, disaster exposure, psychological, and community factors. However, the quantitative evidence linking extreme weather events to mental health was limited due to a lack of longitudinal data, lack of control groups, and the absence of objective exposure measurements. The review found some compelling evidence linking extreme weather events to adverse mental health in the South and Southeast Asia region. Future research should focus on longitudinal study design to identify the specific stressors and climatic factors influencing the relationship between climate extremes and mental health in this region.

Changes in the menstrual hygiene management facilities and usage among Bangladeshi school girls and its effect on school absenteeism from 2014 to 2018.

BACKGROUND: The lack of menstrual hygiene management (MHM) information and facilities in schools is a major contributor to adolescent girls' school absenteeism in low- and middle-income countries like Bangladesh. OBJECTIVES: This paper examines the changes over time in school MHM facilities, knowledge and perceptions among adolescent girls, in relation to school absenteeism between 2014 and 2018 in Bangladesh. METHODS: We examined changes in MHM and school absenteeism among schoolgirls using nationally representative data from the Bangladesh National Hygiene Baseline Survey 2014 and National Hygiene Survey 2018. Given the repetitive nature of our data and its clustering within participants, our method included performing descriptive analysis, bivariate analysis, and multivariate Generalised Estimating Equation (GEE) modelling to analyse these changes. RESULTS: Results showed that adolescent girls' menstruation-related absenteeism decreased between 2014 and 2018. Percentage of adolescents who missed school decreased from 25% to 14% (PD: -11; CI: -16 to -6.1), while the average number of missed days reduced from 2.8 to 2.5 (PD: -0.33; CI: -0.57 to -0.10). In the GEE model, we found that living in rural areas (coef: -5.6; CI: -10.06 to -1.14), parental restrictions on going outside (coef: 4.47; CI: 0.75 to 8.2), education levels of girls (coef: -9.48; CI: -14.17 to -4.79), girl's belief that menstruation affects school performance (coef: 23.32; CI: 19.71 to 26.93), and using old cloths (coef: -4.2; CI: -7.6 to -0.79) were significantly associated with higher absenteeism. However, participant's age, type of school, knowledge of menstruation before menarche, receiving information regarding MHM, separate place for changing absorbents, and separate latrine and urine facility were not significantly associated with the changes in absenteeism over time. CONCLUSION: This paper emphasised the associations between changes in school absenteeism, parental restrictions on students, students' education levels, and menstruation-related misperceptions. Ongoing research, policy reviews, and targeted interventions to improve MHM perceptions among girls are required to provide long-term benefits for adolescent girls in Bangladesh.

Intradermal Delivery of Naked mRNA Vaccines via Iontophoresis.

Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient compliance. Furthermore, side effects such as fever and anaphylaxis associated with the lipid nanoparticle components are also serious problems. Therefore, noninvasive, painless administration of mRNA vaccines that do not contain other problematic components is highly desirable. Antigen-presenting cells reside in the epidermis and dermis, making the skin an attractive vaccination site. Iontophoresis (ItP) uses weak electric current applied to the skin surface and offers a noninvasive permeation technology that enables intradermal delivery of hydrophilic and ionic substances. ItP-mediated intradermal delivery of biological macromolecules has also been studied. Herein, we review the literature on the use of ItP technology for intradermal delivery of naked mRNA vaccines which is expected to overcome the challenges associated with mRNA vaccination. In addition to the physical mechanism, we discuss novel biological mechanisms of iontophoresis, particularly ItP-mediated opening of the skin barriers and the intracellular uptake pathway, and how the combined mechanisms can allow for effective intradermal delivery of mRNA vaccines.

Integrating health belief model and theory of planned behavior to assess COVID-19 vaccine acceptance among urban slum people in Bangladesh.

INTRODUCTION: The vaccination against coronavirus disease 2019 (COVID-19) has been identified as a promising strategy to reduce the severity of the pandemic. Despite the safe and effective COVID-19 vaccines, bringing socioeconomically disadvantaged people under vaccination coverage has been challenging for developing countries like Bangladesh. Therefore, this study explored the determinants of vaccine acceptance among urban slum residents of Bangladesh using the Health Belief Model (HBM) and Theory of Planned Behavior (TPB). METHODS: A face-to-face survey of 400 urban slum dwellers in two large cities in Bangladesh was conducted between July 5 to August 5, 2021. The questionnaire included vaccine acceptance, socio-demographics, health-related characteristics, trust in health authorities, reasons for vaccine hesitancy, and dimensions of HBM and TPB frameworks. Hierarchical logistic regression was performed to evaluate the association between these characteristics and vaccination acceptance. RESULTS: Around 82% (n = 327) of respondents were willing to accept the COVID-19 vaccine. In a fully adjusted model, respondents with secondary level education had higher intention (OR = 46.93, 95%CI = 1.21-1807.90, p < 0. 05) to accept COVID-19 vaccine. Respondents with bad (OR = 0.11, 95%CI = 0.01-0.35, p<0.05) or very bad (OR = 0.01, 95%CI = 0.01-0.35, p<0.05) health conditions were less interested in the COVID-19 vaccination. In regard to HBM dimensions, greater perceived susceptibility (OR = 1.75, 95% CI = 1.12-2.75, p < 0.05), and perceived benefits (OR = 3.28, 95% CI = 1.17-6.00, p < 0.001) were associated with a greater willingness to get vaccinated. In regard to TPB, higher self-efficacy in preventing illness without the vaccine increased the desire to get vaccinated (OR = 1.55, 95% CI = 1.02-2.37, p < 0.05). Fear of unknown side effects, religious beliefs, contraindications to vaccination, and insufficient information on the vaccine were the main reasons for vaccine hesitancy. CONCLUSIONS: These findings offer valuable insights for policymakers in Bangladesh to design targeted interventions that address vaccine hesitancy and increase vaccination acceptability among socially disadvantaged individuals in urban areas. Strategies should focus on providing accurate and accessible information about the vaccine, communicating its positive impact effectively, engaging with religious leaders to address misconceptions, and tailoring vaccination campaigns to meet the unique needs of different demographic groups.

Astrocyte and L-lactate in the anterior cingulate cortex modulate schema memory and neuronal mitochondrial biogenesis.

Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic Gi signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and schema memory is not clear. Here, using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic Gi pathway activation in the ACC causes significant impairments in flavor-place paired associates (PAs) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments are mediated by decreased L-lactate in the ACC due to astrocytic Gi activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation is associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in the ACC upon astrocytic Gi activation. Our study also reveals that L-lactate-mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 (MCT2) and NMDA receptor activity - discovering a previously unrecognized signaling role of L-lactate. These findings expand our understanding of the role of astrocytes and L-lactate in the brain functions.

Ciprofloxacin and Tetracycline Resistance Cause Collateral Sensitivity to Aminoglycosides in Salmonella Typhimurium.

The objective of this study was to evaluate collateral sensitivity and cross-resistance of antibiotic-induced resistant Salmonella Typhimurium to various antibiotics. S. Typhimurium ATCC 19585 (STWT) was exposed to ciprofloxacin, gentamicin, kanamycin, and tetracycline to induce antibiotic resistance, respectively, assigned as STCIP, STGEN, STKAN, and STTET. The susceptibilities of the antibiotic-induced resistant mutants to cefotaxime, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, polymyxin B, streptomycin, tetracycline, and tobramycin were determined in the absence and presence of CCCP and PAßN. STCIP showed the cross-resistance to tetracycline and collateral sensitivity to gentamicin (1/2 fold) and kanamycin (1/4 fold). STTET was also cross-resistant to ciprofloxacin (128-fold) and collateral sensitive to gentamicin (1/4-fold) and kanamycin (1/8-fold). The cross-resistance and collateral sensitivity of STCIP and STTET were associated with the AcrAB-TolC efflux pump and outer membrane porin proteins (OmpC). This study provides new insight into the collateral sensitivity phenomenon, which can be used for designing effective antibiotic treatment regimens to control antibiotic-resistant bacteria.

Assessment of the potential of phage-antibiotic synergy to induce collateral sensitivity in Salmonella Typhimurium.

This study was designed to evaluate the synergistic effect of phage and antibiotic on the induction of collateral sensitivity in Salmonella Typhimurium. The synergistic effects of Salmonella phage PBST32 combined with ciprofloxacin (CIP) against S. Typhimurium KCCM 40253 (STKCCM) were evaluated using a fractional inhibitory concentration (FIC) assay. The CIP susceptibility of STKCCM was increased when combined with PBST32, showing 16-fold decrease at 7 log PFU/mL. The combination of 1/2 × MIC of CIP and PBST32 (CIP[1/2]+PBST32) effectively inhibited the growth of STKCCM up to below the detection limit (1.3 log CFU/mL) after 12 h of incubation at 37 °C. The significant reduction in bacterial swimming motility was observed for PBST32 and CIP[1/4]+PBST32. The CIP[1/4]+PBST32 increased the fitness cost (relative fitness = 0.57) and decreased the cross-resistance to different classes of antibiotics. STKCCM treated with PBST32 alone treatment exhibited the highest coefficient of variation (90%), followed by CIP[1/4]+PBST32 (75%). These results suggest that the combination of PBST32 and CIP can be used to control bacterial pathogens.

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.

L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate's beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.

Protective effects of liposomes encapsulating ferulic acid against CCl4-induced oxidative liver damage in vivo rat model.

Antioxidants are useful for the treatment of oxidative stress mediated liver damage. A naturally occurring antioxidant γ-oryzanol is rapidly hydrolyzed to its active hydrophobic metabolite, ferulic acid, inside the body. Limitations associated with the hydrophobicity of ferulic acid can be overcome by encapsulating in a liposomal formulation. As intravenously administered nanoparticles (including liposomes) can effectively reach the liver, such systems may be suitable drug delivery carriers to treat liver injury. In this study, we prepared a liposomal formulation of ferulic acid (ferulic-lipo) and examined its effects on liver damage induced by CCl4. Ferulic-lipo were ~100 nm in size and drug encapsulation efficiency was about 92%. Ferulic-lipo showed potent scavenging efficacy against hydroxyl radical compared to α-tocopherol liposomes. Ferulic-lipo significantly prevented CCl4-mediated cytotoxicity in human hepatocarcinoma cells. Furthermore, intravenous administration of ferulic-lipo significantly reduced alanine aminotransferase and aspartate amino transferase levels in a rat model of liver injury. CCl4-mediated reactive oxygen species generation in liver was also reduced by intravenous administration of ferulic-lipo. Hepatoprotective effects of ferulic-lipo were demonstrated by histological observation of CCl4-induced liver tissue damage. Therefore, ferulic-lipo exhibit potent antioxidative capacity and were suggested to be an effective formulation for prevention of oxidative damage of liver tissue.

Erratum: Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats.

[This corrects the article DOI: 10.1016/j.isci.2022.105840.].

Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats.

Using a well-established chronic visceral hypersensitivity (VH) rat model, we characterized the decrease of myelin basic protein, reduced number of mature oligodendrocytes (OLs), and hypomyelination in the anterior cingulate cortex (ACC). The results of rat gambling test showed impaired decision-making, and the results of electrophysiological studies showed desynchronization in the ACC to basolateral amygdala (BLA) neural circuitry. Astrocytes release various factors that modulate oligodendrocyte progenitor cell proliferation and myelination. Astrocytic Gq-modulation through expression of hM3Dq facilitated oligodendrocyte progenitor cell proliferation and OL differentiation, and enhanced ACC myelination in VH rats. Activating astrocytic Gq rescued impaired decision-making and desynchronization in ACC-BLA. These data indicate that ACC hypomyelination is an important component of impaired decision-making and network desynchronization in VH. Astrocytic Gq activity plays a significant role in oligodendrocyte myelination and decision-making behavior in VH. Insights from these studies have potential for interventions in myelin-related diseases such as chronic pain-associated cognitive disorders.

Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive behaviour. ACC astrocytic Gi manipulation suppressed aversive behaviour and early plasticity gene expression induced by opto-activation of LC neurons projecting to ACC. Evidences for the critical role of ß2AR in ACC astrocytes were provided using AAV encoding ß2AR miRNAi to knockdown ß2AR in astrocytes. In contrast, opto-activation of ACC astrocytic ß2ARs promotes aversion memory. Our findings suggest that projection-specific adrenergic astrocytic signalling in ACC is integral to system-wide neuromodulation in response to visceral stimuli, and plays a key role in mediating pain-related aversion consolidation and memory formation.

Psychological determinants of COVID-19 vaccine acceptance among urban slum dwellers of Bangladesh.

Introduction: Coronavirus disease 2019 (COVID-19) vaccination has emerged as a promising approach to counter the harmful impacts of the pandemic. Understanding the psychological components that may impact an individual's attitude toward COVID-19 vaccination is crucial for generating evidence-based ways to minimize vaccine hesitancy. This study determined the psychological antecedents regarding vaccine acceptance among urban slum people of Bangladesh. Methods: From 5 July to 5 August 5, 2021, a face-to-face survey was conducted in the urban slum of two large cities in Bangladesh. The questionnaire considered socio-demographics, health-related characteristics, psychological determinants, sources of information, and conspiracy beliefs regarding COVID-19. The 5C sub-scales were used to assess psychological antecedents. Five stepwise binary logistic regression models evaluated significant predictors for confidence, complacency, calculation, constraints, and collective responsibility. Multinomial logistic regression was used to determine the relationship between psychological antecedents and vaccine acceptability. Results: The study revealed that the slum residents with a high level of confident (89.94%), complacent (72.73%), having constraints (82.31%), calculative (84.80%), and responsible (93.30%) showed a higher vaccine acceptance rate. Higher vaccine acceptance was related to the believer in natural-made origin (85.96%) and those who rejected anti-vaccination (88.44%). The information acquired from newspapers differed significantly (p < 0.05), though TV or radio was the most common primary information source about COVID-19 vaccines (74.75%). The regression result revealed that marital status, education, family income, and perceived health condition were significantly associated with the 5C domains. Two psychological antecedents including complacency (OR = 3.97; p < 0.001) and collective responsibility (OR = 0.23; p < 0.001) were significantly associated with vaccine acceptance. Conclusions: Different predictors significantly affect psychological antecedents related to COVID-19 vaccine uptake. Therefore, considering the factors, targeted actions based on the findings may help to lower vaccine reluctance and boost vaccination rates.

Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria.

With the increasing global threat of antibiotic resistance, there is an urgent need to develop new effective therapies to tackle antibiotic-resistant bacterial infections. Bacteriophage therapy is considered as a possible alternative over antibiotics to treat antibiotic-resistant bacteria. However, bacteria can evolve resistance towards bacteriophages through antiphage defense mechanisms, which is a major limitation of phage therapy. The antiphage mechanisms target the phage life cycle, including adsorption, the injection of DNA, synthesis, the assembly of phage particles, and the release of progeny virions. The non-specific bacterial defense mechanisms include adsorption inhibition, superinfection exclusion, restriction-modification, and abortive infection systems. The antiphage defense mechanism includes a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system. At the same time, phages can execute a counterstrategy against antiphage defense mechanisms. However, the antibiotic susceptibility and antibiotic resistance in bacteriophage-resistant bacteria still remain unclear in terms of evolutionary trade-offs and trade-ups between phages and bacteria. Since phage resistance has been a major barrier in phage therapy, the trade-offs can be a possible approach to design effective bacteriophage-mediated intervention strategies. Specifically, the trade-offs between phage resistance and antibiotic resistance can be used as therapeutic models for promoting antibiotic susceptibility and reducing virulence traits, known as bacteriophage steering or evolutionary medicine. Therefore, this review highlights the synergistic application of bacteriophages and antibiotics in association with the pleiotropic trade-offs of bacteriophage resistance.

A flavone from the ethyl acetate extract of Leea rubra leaves with DNA damage protection and antineoplastic activity.

Among the major constituents of Leea rubra (Family Vitaceae) leaves, phenolic and flavonoind compounds are most important for therapeutic purposes and the plant parts have been used in traditional medicine to treat several diseases for long. Thus, in order to scientifically confirm the traditional uses of the L. rubra leaves, the present study was designed to investigate the efficacy of the isolated flavones against AAPH induced oxidative damage to pUC19 DNA by gel electrophoresis and antineoplastic activity was evaluated on Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice by evaluating percentage inhibition of cell growth, morphological changes of EAC cells and hematological parameters of the mice. The isolation was carried out by column chromatography and structure was revealed by 1H-NMR and 13C NMR. The result shows that, the isolated compound was identified as myricetin 4'-methoxy-3-O-α-l-rhamnopyranoside based on previously reported data. The isolated flavone effectively inhibited AAPH-induced oxidative damage to DNA; because it could inhibit the formation of circular and linear forms of the DNA. In anti-proliferative assay, 76% growth inhibition of EAC cells was observed as compare to the control mice (p<0.05) at a dose 100 mg/kg body weight. Thus the isolated flavone showed great importance as a possible therapeutic agent in preventing oxidative damage to DNA and the chronic diseases caused by such DNA damage, and can also become important in cancer chemotherapy.

Iontophoresis of Biological Macromolecular Drugs.

Over the last few decades, biological macromolecular drugs (e.g., peptides, proteins, and nucleic acids) have become a significant therapeutic modality for the treatment of various diseases. These drugs are considered superior to small-molecule drugs because of their high specificity and favorable safety profiles. However, such drugs are limited by their low oral bioavailability and short half-lives. Biological macromolecular drugs are typically administrated via invasive methods, e.g., intravenous or subcutaneous injections, which can be painful and induce needle phobia. Noninvasive transdermal delivery is an alternative administration route for the local and systemic delivery of biological macromolecular drugs. However, a challenge with the noninvasive transdermal delivery of biological macromolecular drugs is the outermost layer of the skin, known as the stratum corneum, which is a physical barrier that restricts the entry of extraneous macromolecules. Iontophoresis (IP) relies on the application of a low level of electricity for transdermal drug delivery, in order to facilitate the skin permeation of hydrophilic and charged molecules. The IP of several biological macromolecular drugs has recently been investigated. Herein, we review the IP-mediated noninvasive transdermal delivery of biological macromolecular drugs, their routes of skin permeation, their underlying mechanisms, and their advance applications.

Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways.

Nanoparticle drug carriers have been employed to achieve systemic delivery of nucleic acid therapeutics, including small interfering RNA (siRNA); however, non-specific distribution and immune-related events often cause undesired adverse effects. Thus, there is a need for a new technology capable of specifically delivering nucleic acid therapeutics to desired sites. We demonstrated the utility of iontophoresis (IP) using weak electric current (0.3-0.5 mA/cm2) as a local drug delivery technology. Our previous studies revealed that IP allows for transdermal permeation of nucleic acid therapeutics via induction of intercellular junction cleavage initiated by Ca2+ influx-mediated cellular signaling activation, and subsequent cytoplasmic delivery through a unique endocytosis process in both skin and other cells. Based on these findings, we hypothesized that IP may enable direct delivery of nucleic acid therapeutics to internal organs through non-blood circulatory pathways without the use of delivery carriers. Permeation of fluorescent-labeled nucleic acids administered via IP applied to the surface of the liver and pancreas was observed in both organs, but not with topical application. IP-mediated local delivery of siRNA into the liver and pancreas significantly suppressed target mRNA expression in each organ. Moreover, IP administration of therapeutic siRNA against the molecules responsible for liver steatosis and fibrosis significantly inhibited lipid accumulation and fibrotic hepatic damage in individual model mice. These findings suggest that IP may be a useful technology to directly deliver nucleic acid therapeutics to internal organs without use of drug delivery carriers via non-blood circulatory pathways.